Age is a prison

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The genetics of ageing in worms and humans.

It was once said that age is a prison from which no man can escape. Nevertheless scientists are trying their best to understand this feared process that haunts so many. People are familiar with what it is like to grow old, but when it comes to comprehending the intricate causes of ageing, the scientific community is still unable to reach a conclusion. Amongst the wide range of model organisms being used to study gerontology, the free living soil nematode Caenorhabditis elegens appears to be the organism of choice. There are many reasons behind this. Approximately 1mm in length, it has a rapid life cycle that lasts 3-4 days and it can produce a large number of offspring that ranges from 300 to 1000. (Wood, William Barry. 1988). There are two sexes, males and hermaphrodites. The hermaphrodites are self fertilizing, resulting in progeny full of genetically recessive mutants that are easy to isolate. (Brenner, S. May 1974).

One such genetic mutation, daf-2, results in mutants whose life span whose lifespan is twice as long as their wild type counterparts. This mutation affects one stage of the larval process; the Dauer larvae. These Dauer larvae generally exist in adverse conditions such as high temperature, high population density and food scarcity. The daf-2 mutants form Dauers even when such environmental pressures are not present, giving rise to adults that are stress resistant and long lived. (Ricklefs, R., Finch, C. 1995). It has also been established that a loss of function mutation in daf-16 suppresses daf-2, resulting in a short lived organism. Thus the daf-16 wild type promotes daf-2 resulting in a long lived mutant. Thus daf-16 could be identified as the longevity gene. But how does daf-2 prolong life in C. elegens? The daf-2 gene codes for a cell surface receptor which is homologous to the mammalian insulin-like growth factor (IGF-1) receptors. Daf-2(+) increases Insulin/IGF-1 signalling (IIS) and results in a shorter life span. Daf-2(-) decreases Insulin/IGF-1 signalling and results in a longer life span. Therefore it could be concluded that reduced IIS increases longevity. (Partridge, Gems, Tartar labs)

Another mutation age-1, is thought to increase the average life span of C. elegens by approximately 65%, whilst causing a 75% reduction in the fertility of self fertilising hermaphrodites. age-1 codes for the homologue of a catalytic subunit of a lipid kinase, phosphatidylinositol 3-OH kinase (PI3K). In theory, PI3K is then used to produce PIP3 from PIP2. PIP3 then enlists kinases such as AKT-1. The activity of such kinases results in the regulation of DAF-16 which is the target of DAF-2 and AGE-1. DAF-2 indirectly suppresses DAF-16 by phosphorylating it via AKT-1. Therefore in mutants, DAF-16 is not suppressed as there is a decrease in signalling. This leads to an extended life span.

However there are many other hypotheses regarding ageing. One example is the free radical theory of aging. The title is faintly misleading as both free radicals and non-radicals are involved. This theory states that a build-up of Reactive Oxygen Species (ROS) can cause severe molecular damage. Some examples of ROS are superoxide and hydroxyl (free radicals), and hydrogen peroxide and hypochlorous acid (non-radical). ROS can also take advantage of weak antioxidant defences such as lower levels of superoxide dismutase. The chemistry of ROS is quite complex and wide ranging, however the 3 most important outcomes are the oxidation of DNA, the oxidation of proteins and the peroxidation of lipids. The amount of damage in DNA, proteins and lipids increases with age. One piece of evidence that endorses this theory is the increased level of antioxidants superoxide dismutase and catalase which may negate the effects of ROS that are present in the age-1 mutants and Dauer larvae.

Another theory is that of cellular senescence. Hayflick proposed that ageing takes place on a cellular level, as opposed to an organismal level. He observed that there was a limit to the number of times a cell can replicate. This figure is now known as the Hayflick limit. (Hayflick and Moorhead, 1961). The foundation of this theory is based on telomeres. They are repeated strands of DNA that do not code for any proteins and are found at the ends of eukaryotic chromosomes. Chromosomes that are not capped by telomeres are found to be particularly recombinogenic; they are likely to give rise to recombinant DNA. Succeeding each cell division, a section of these telomeres is lost as they cannot be copied. 50-200 terminal base pairs are lost during each cell division (Harley et al. Nature 1990). Once the telomeres reach a critical length after numerous cell divisions, the cell commits itself to apoptosis, or programmed cell death. This is to prevent any further replicating errors that would result in DNA mutations. However, the enzyme telomerase has the ability to replace lost telomeres. This enzyme is a RNA dependant polymerase, also known as a reverse transcriptase. Telomerase re-forms telomeres, thereby potentially allowing cells to replicate an unlimited number of times. () Absent in human somatic cells, telomerase is found in cancerous cells thus explaining why the growth/replication of cancerous cells does not fall victim to the Hayflick limit. () Interestingly, telomeres are particularly susceptible to oxidative damage due to their 'TTAGGG' structure, of which 'GGG' is particular vulnerable to oxidative damage. () This gives further credence to the Free radical/ROS theory of ageing.

Centenarians have been utilized in research as well. One gene they were tested for was the ApoE gene, which codes for the protein apolipoprotein E. This gene is polymorphic and so has 3 forms ApoE2, ApoE3 and ApoE4. When the allelic frequency was determined, the centenarians had a higher frequency of the ApoE2 allele and a shortage of the ApoE4 allele when compared with the controls. Thus it could be inferred that ApoE2 increases longevity. This suggestion is reinforced by the case of individuals who have 2 mutant alleles of ApoE and are therefore deficient for all APoE proteins. They are at high risk of developing atherosclerosis and hyperlipidemia (excess lipids in the blood). Thus, the existence of normal ApoE alleles and their relevant proteins prevents premature death.